Preparing the methoxymethyl ether of a phenol is a well-known method for protecting phenolic hydroxyl groups from unwanted reactions [see, for example, L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, p. 133, John Wiley and Sons, Inc., New York, New York, 1967; J. F. W. McOmie, Advances in Organic Chemistry, 3, 232 (1963)]. The reagent most often utilized in the prior art to effect this transformation has been chloromethyl methyl ether. However, since this substance has recently been indicated as possessing a carcinogenic potential [Federal Register, 39, 3757 (1974)], its use as a reagent has become less desirable. The only remaining, art-recognized, reagent which is utilized in a one-step preparation of methoxymethyl ethers is methoxymethyl methanesulfonate (U.S. Pat. No. 3,737,449). This substance has been described as a corrosive and extremely hygroscopic liquid, thus necessitating special techniques for its use and manipulation, which techniques may often be inconvenient and time-consuming.
The instant invention advantageously provides an alternative procedure for the conversion of phenols to their methoxymethyl ether derivatives. This procedure has the additional advantage of utilizing for this conversion, the readily available, unobjectionable reagent, dimethoxymethane.
The phenol methoxymethyl ethers, preparable by the instant process, are useful as reaction intermediates when it is desired to protect the phenol function from an unwanted reaction and subsequently regenerate the phenol [see, for example, Belgian Patent 797,827; R. L. Edwards and I. Mir, J. Chem Soc. (c), 411 (1967); M. A. Abdel-Rahman, H. W. Elliot, R. Binks, W. Kunig, and H. Rapoport, J. Med. Chem., 9, 1 (1965)]. Of particular interest and importance is the protected phenol, m-methoxymethoxybenzaldehyde, an intermediate used in the synthesis of several potent analgesic compounds (Belgian Patent 797,827); one such compound is 1-cis-2-(.alpha.-dimethylamino-m-hydroxybenzyl)cyclohexanol.